FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
AND
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION
"Film composition containing buprenorphine and naloxone"
2. APPLICANT
(a) NAME: Raptim Research Ltd.
(b) NATIONALITY: An Indian Organization
(c) ADDRESS: A-226, TTC Industrial Area, Mahape MIDC, Navi Mumbai 400701
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the Invention
The present invention relates, in general, to the field of pharmaceutical compositions and, in particular, to pharmaceutical film compositions containing buprenorphine HCI and naloxone HCI for sublingual administration to a patient in need for the treatment of opioid/narcotic dependence.
Background of the Invention
Buprenorphine, chemically described as N-cyclopropylmethyl-7a-[1-(S)-hydroxy-1, 2, 2-trimethylpropylJ 6, 16-endoethano-6, 7, 8, 14-tetrahydronororipavine, is a potent opiate partial agonist analgesic that lack the pyschotomimetic effects ordinarily found with the other opiate analgesics. It has the following chemical structure:

However, buprenorphine produce typical opioid agonist effects such as nausea and vomiting, euphoria and respiratory depression in patients. There had been various attempts to enhance analgesic effect of buprenorphine while minimizing the incidence and severity of adverse effects and one such known approach is the coadministration of buprenorphine with an opioid antagonist, such as, naloxone which has the following chemical structure:

Naloxone, chemically described as 1-N-allyl-14-hydroxynorhydro morphinone, is a narcotic antagonist which has been formulated into oral and sublingual preparations of buprenorphine to protect the preparation from parenteral abuse while maintaining the analgesic effect of buprenorphine.

GB2150832 teaches analgesic composition in sublingual or parenteral dosage form of buprenorphine with sufficient amount of naloxone to prove aversive to a narcotic addict by parenteral administration but insufficient to comprise the analgesic action of the buprenorphine.
EP1242087B1 teaches analgesic composition in parenteral unit dosage form or in a unit dosage form suitable for delivery via mucosa comprising buprenorphine in an amount less than the clinical dose required to achieve pain relief and naloxone in an amount such that the ratio of buprenorphine to naloxone is in the range of from 12.5:1 to 27.5:1. The analgesic action of buprenorphine is potentiated by the low dose of naloxone.
US20110033541A1 teaches film composition containing a polymeric carrier matrix, therapeutic effective amount of buprenorphine and naloxone, and a buffer in an amount to provide a pH of the composition of a value sufficient to optimize absorption of the buprenorphine.
Despite these advances in the art, there remains a need for reasonably simpler and more practical sublingual film compositions of buprenorphine and naloxone for the treatment of opioid/narcotic dependence.
Summary of the Invention
The present invention provides film compositions comprising buprenorphine and naloxone for sublingual administration to a patient in need for the treatment of opioid/ narcotic dependence. In a preferred embodiment, the film composition comprises buprenorphine hydrochloride and naloxone hydrochloride with pharmaceutically acceptable excipients.
Detailed Description of the Invention
The invention relates to pharmaceutical compositions Containing buprenorphine and naloxone for sublingual administration to a patient. The composition of the invention is administered to a patient in need for the maintenance treatment of opioid/narcotic dependence, and provides a bioequivalent effect to the reference standard product, i.e. Suboxone®.
The following disclosure describes the composition which constitutes the invention. The invention is not limited to the specific composition described herein, as such

may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural references unless the context clearly dictates otherwise.
Unless defined otherwise, all technical and scientific terms as used herein have the ordinary meaning as understood by those skilled in the art to which this invention belongs.
The term "active agent", "active ingredient" and "drug" are used interchangeably and include combination of buprenorphine and naloxone.
The term "AUC" refers to the area under a plasma concentration versus time curve obtained during the dosing interval.
The term "bJoequivaJent" or "bioequivaJence" refers to, by way of non-iimiting example, a drug product or a pharmaceutical composition that, upon administration to a patient, provides calculated 90% confidence interval for AUC and Cmax in the range of 80% to 125% of those provided by a reference standard.
The term !'Cmax" refers to the maximum concentration obtained during the dosing interval.
The term "composition", "sublingual film composition" and "film composition" are used Interchangeably and refer to a composition containing buprenorphine and naioxone for sublingual administration to a patient.
The term "dissolution" refers to the process by which the active ingredient is dissolved from the film composition in the presence of a solvent, in vitro, or physiological fluid in vivo, e.g. saliva.
The term "sublingual" refers to a method of administering substances via mouth in such a way that the substances are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract.

(n preferred embodiment, the invention provides a film composition comprising buprenorphine hydrochloride and naloxone hydrochloride for administration to a patient sublingually. In addition to buprenorphine hydrochloride and naloxone hydrochloride, the film composition contains pharmaceutically acceptable excipients that include polyvinyl alcohol polyethylene glycol graft copolymer, maltitol, acesulfame potassium and citric acid.
The following examples illustrate various aspects of the present, but should not be understood to limit the scope of the invention.
Example 1
Film composition of buprenorphine and naloxone
Two different strengths of sublingual film composition containing buprenorphine and
naloxone were prepared having the ratio by weight of buprenorphine to naloxone is
8:2 and 2:0.5. The ingredients of the film composition are listed in Table 1 and 2.
TABLE 1

Ingredients mg/film
Buprenorphine hydrochloride 8.64
Na)oxone hydrochloride dihydrate 2.44
Polyvinyl alcohol polyethylene glycol graft copolymer 66.67
Maltitol 10
Acesulfame potassium 1.0
Lime flavour 0.1
FD&C yellow 0.13
Citric acid 0.5
Total weight 89.48
The ratio by weight of buprenorphine hydrochloride and naloxone hydrochloride dihydrate in above table is 8:2.
TABLE 2

Ingredients mg/film
Buprenorphine hydrochloride 2.18

Naloxone hydrochloride dihydrate
0.65
Polyvinyl alcohol polyethylene glycol graft copolymer 61.21
Maltitol 9.8
acesulfame potassium 1.0
Lime flavour 0.1
FD&C yellow 0.11
Citric acid 0.5
Total weight 75.55
The ratio of buprenorphine hydrochloride and naloxone hydrochloride dihydrate in above table is 2:0.5.
Example 2
Dissolution: Comparative Studies
Dissolution profile of both the reference standard product Suboxone® (8mg
buprenorphine and 2mg naloxone) and the film composition (Table 1) of the present
invention were compared and tested in vitro at pH 3.5 according to the US
Pharmacopeia, using USP Apparatus 1 (Basket) at 100 rpm in 500ml of 0.1
hydrochloric acid at 37°C. The dissolution results are set forth in Table 1 A.
TABLE 1A

Time (minutes) % of Buprenorphine Dissolved % of Naloxone Dissolved

Table 1 Suboxone® Table 1 Suboxone®
0 0 0 0 0
1 19 22 21 20
2 47 46 45 42
5 101 101 100 100
The dissolution results indicate in vitro bioequivalence of the film composition (Table 1) of the present invention to that of the reference product (Suboxone®).
Similarly, dissolution profile of both the reference standard product Suboxone® (2mg buprenorphine and 0.5mg naloxone) and the film composition (Table 2) of the present invention were compared and tested in vitro at pH 3.5 according to the US

Pharmacopeia, using USP Apparatus 1 (Basket) at 100 rpm in 500ml of 0.1 hydrochloric acid at 37°C. The dissolution results are set forth in Table 2A.
TABLE 2A

Time (minutes) % of Buprenorphine Dissolved % of Naloxone Dissolved

Table 2 Suboxone® Table 2 Suboxone®
0 0 0 0 0
1 21 18 23 22
2 49 47 47 45
5 101 100 100 100
The dissolution results indicate in vitro bioequivalence of the film composition (Table 2) of the present invention to that of the reference product (Suboxone®).
Example 3
Pharmacokinetic Profile: In vivo studies
Pharmacokinetic profile of both the reference standard product Suboxone® (8mg
buprenorphine and 2mg naloxone) and the film composition (Table 1) of the present
invention were compared and tested in vivo for absorption data. The absorption data
are set forth in Table 1B.
TABLE 1B

Parameter Buprenorphine Naloxone

Table 1 Suboxone® Table 1 Suboxone®
Cmax 4.222 ng/ml 3.876 ng/ml 48.8143 ng/ml 52.1607 ng/ml
AUC 23.549 hr*ng/ml 22.500 hr*ng/ml 177.3204
hr*ng/ml 179.1186
hr* ng/ml
As can be seen, the in vivo data indicated that the absorption of buprenorphine and naloxone were comparable to Suboxone and provide a bioequivalent effect as the reference product (Suboxone®).
Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art

upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims
1. A pharmaceutical composition comprising polyvinyl alcohol polyethylene glycol graft copolymer, buprenorphine hydrochloride and naloxone hydrochloride dihydrate.
2. The composition as claimed in claim 1, wherein the ratio by weight of buprenorphine hydrochloride to naloxone hydrochloride dihydrate is 8:2.
3. The composition as claimed in claim 1, wherein the ratio by weight of buprenorphine hydrochloride to naloxone hydrochloride dihydrate is 2:0.5.
4. The composition as claimed in claim 1, wherein the composition is in the form of a film.
5. The composition as claimed in claim 1 further comprises citric acid, maltitol and acesulfame potassium.
6. The composition as claimed in claim 1 is administered sublingually.
7. The composition as claimed in claim 1 is administered sublingually for the treatment of opioid dependence.